(1) Field of the Invention
The present invention relates to a crystal of a 4(3H)-quinazolinone derivative, more precisely to a form I crystal of 2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone.
(2) Description of Related Art
It has been known that, in organisms such as typically mammals, histamine that is a physiologically-active endogenous factor functions as a neurotransmitter and has extensive pharmacological activities (for example, see Non-Patent Reference 1).
Immunohistochemical studies have made it clear that a histamine-agonistic (producing) cell body exists in the nodal papillary nucleus in a posterior hypothalamic region and that histamine nerve fibers project in an extremely broad range in a brain, which supports various pharmacological effects of histamine (for example, see Non-Patent Reference 2). The existence of histamine-agonistic nerves in the nodal papillary nucleus in a posterior hypothalamic region suggests that histamine may have an important role in control of physiological functions relating to brain functions, especially to hypothalamic functions (sleep, vigilance rhythm, incretion, eating and drinking behavior, sexual action, etc.) (for example, see Non-Patent Reference 3).
The existence of the projection in the brain region that relates to vigilance sustenance, for example, in a cerebral cortex suggests the role in regulation of vigilance or vigilance-sleep cycle. The existence of the projection in many peripheral structures such as hippocampus and amygdaloid complex suggests the role in regulation of autonomic nerves, emotion, control of motivated action and learning/memory process.
When released from producing cells, histamine reacts with a specific polymer that is referred to as a receptor on the surface of a cell membrane or inside a target cell, therefore exhibiting its pharmacological effects for regulation of various body functions. Heretofore, four types of histamine receptors have been found. In particular, the presence of a histamine receptor that participates in the central and peripheral nervous functions, a histamine-H3 receptor, has been shown by various pharmacological and physiological studies (for example, see Non-Patent Reference 4). Recently, human and rodent histamine-H3 receptor genes have been identified and their existence has been revealed (for example, see Non-Patent Reference 5).
It is shown that the histamine-H3 receptor exists in the presynaptic membrane of central or peripheral neurocytes and functions as a self-receptor, therefore controlling the release of histamine and controlling even the release of other neurotransmitters. Specifically, it is reported that a histamine-H3 receptor agonist, or its antagonist or inverse-agonist regulates the release of histamine, noradrenaline, serotonin, acetylcholine or dopamine from nerve terminal. For example, the release of these neurotransmitters is inhibited by an agonist such as (R)-(α)-methylhistamine, and is promoted by an antagonist or inverse-agonist such as thioperamide (for example, see Non-Patent Reference 6).    Patent Reference 1: German Patent 1,939,109,    Patent Reference 2: U.S. Pat. No. 5,948,775,    Non-Patent Reference 1: Life Science, Vol. 17, p. 503 (1975),    Non-Patent Reference 2: Journal of Comprehensive Neurology, Vol. 273, p. 283,    Non-Patent Reference 3: Progress in Neurobiology, Vol. 63, p. 637 (2001),    Non-Patent Reference 4: Trends in Pharmacological Science, Vol. 8, p. 24 (1986),    Non-Patent Reference 5: Molecular Pharmacology, Vol. 55, p. 1101 (1999),    Non-Patent Reference 6: Trends in Pharmacological Science, Vol. 19, p. 177 (1998).